Myocardial failure is a major cause of morbidity and mortality following myocardial infarction. Despite the longstanding use of digitalis glycosides as the predominant therapy for myocardial failure, their use for the inotropic support of the failing heart after myocardial ischemic injury is controversial. This controversy results primarily from an uncertainty regarding the arrhythmogenic potential of the digitalis glycosides in the setting of ischemic injury. Thus far clinical investigations have failed to unequivocally resolve the issue of such an adverse, proarrhythmic potential of digitalis after ischemia injury. Basic experimental studies conducted to-date suggest an enhanced cardia sensitivity to the arrhythmogenic actions of digitalis after myocardial ischemia/infarction, but offer little relevence to the clinical situation due to the invariable use of rapidly administered, toxic doses of digitalis preparations to assess myocardial sensitivity. A major obstacle in assessing the proper use of digitalis in the setting of myocardial ischemia/infarction has been the lack of an appropriate evaluation of the arrhythmogenic potential of digitalis in therapeutic serum concentrations in an adequate animal model of myocardial ischemic injury. In preliminary studies described in this proposal, conscious dogs in the subacute phase of myocardial infarction have been utilized to demonstrate a significantly increased incidence of lethal ventricular arrhythmias occurring in the presence of therapeutic serum concentrations of digoxin, achieved by chronic daily administration. Based upon this preliminary work, continuing studies in related animal models of ischemic injury are proposed in order to determine the electrophysiologic and neural bases of the arrhythmogenic actions of therapeutically administered digitalis. The long term goal of such studies is the determination of the relative hazards and potential means of reducing the arrhythmogenic risks involved in the use of digitalis in the ischemically-injured heart.